A potent proresolving mediator 17R-resolvin D2 from human macrophages, monocytes, and saliva.

Production of specialized proresolving mediators (SPMs) during the resolution phase in the acute inflammatory response is key to orchestrating complete resolution. Here, we uncovered a trihydroxy resolvin in fresh human saliva. We identified and determined its complete stereochemistry as 7S,16R,17R-trihydroxy-4Z,8E,10Z,12E,14E,19Z-docosahexaenoic acid (17R-RvD2) using total organic synthesis and matching of physical properties.

Biosynthesis of resolvin D1, resolvin D2, and RCTR1 from 7,8(S,S)-epoxytetraene in human neutrophils and macrophages.

While the acute inflammatory response to harmful stimuli is protective, unrestrained neutrophil swarming drives collateral tissue damage and inflammation. Biosynthesized from omega-3 essential polyunsaturated fatty acids, resolvins are a family of signaling molecules produced by immune cells within the resolution phase to orchestrate return to homeostasis. Understanding the mechanisms that govern biosynthesis of these potent molecules gives insight into stimulating endogenous resolution and offers fresh opportunities for preventing and treating excessive inflammation.

Resolvin D2 attenuates LPS-induced macrophage exhaustion.

Early in sepsis, a hyperinflammatory response is dominant, but later, an immunosuppressive phase dominates, and the host is susceptible to opportunistic infections. Anti-inflammatory agents may accelerate the host into immunosuppression, and few agents can reverse immunosuppression without causing inflammation. Specialized pro-resolving mediators (SPMs) such as resolvin D2 (RvD2) have been reported to resolve inflammation without being immunosuppressive, but little work has been conducted to examine their effects on immunosuppression.

Lipoxin A promotes antibiotic and monocyte bacterial killing in established Pseudomonas aeruginosa biofilm formed under hydrodynamic conditions.

Pseudomonas aeruginosa is a gram-negative, opportunistic bacteria commonly found in wounds and in lungs of immunocompromised patients. These bacteria commonly form biofilms which encapsulate the bacteria, making it difficult for antibiotics or immune cells to reach the bacterial cells. We previously reported that Lipoxin A (LxA ), a Specialized Pro-resolving Mediator, has direct effects on P.

Stereochemistry and functions of the new cysteinyl-resolvin, 4S,5R-RCTR1, in efferocytosis and erythrophagocytosis of human senescent erythrocytes.

Specialized pro-resolving lipid mediators play key functions in the resolution of the acute inflammatory response. Herein, we elucidate the stereochemical structure of the new 4S,5R-RCTR1, a cysteinyl-resolvin, recently uncovered in human leukocytes incubated with a 4S,5S-epoxy-resolvin intermediate, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and ultra-violet (UV) spectrophotometry. With this approach, the physical properties of the new mediator prepared by total organic synthesis were matched to enzymatically produced biogenic material.

Resolvin D2 induces anti-microbial mechanisms in a model of infectious peritonitis and secondary lung infection.

In severe bacterial infections, there is a pro-inflammatory response to promote bacterial clearance but this response can cause tissue injury. Later, the immune system becomes dysregulated and the host is unable to clear a secondary or a pre-existing infection. Specialized Pro-resolving Mediators (SPMs) such as resolvin D2 (RvD2) have been shown to be beneficial for inflammation/infection resolution in animal models of sepsis but mechanisms by which RvD2 may promote bacterial clearance and/or attenuate deleterious effects of a secondary infection have not been fully established.

MCTR3 reprograms arthritic monocytes to upregulate Arginase-1 and exert pro-resolving and tissue-protective functions in experimental arthritis.

Background: Rheumatoid arthritis (RA) is a progressive degenerative disorder that leads to joint destruction. Available treatments only target the inflammatory component with minimal impact on joint repair. We recently uncovered a previously unappreciated family of pro-resolving mediators, the maresin conjugate in tissue regeneration (MCTR), that display both immunoregulatory and tissue-protective activities.

Resolvin D2 promotes host defense in a 2 - hit model of sepsis with secondary lung infection.

In the development of sepsis, there is early, massive inflammation which can lead to multiple organ failure. Later there is an immunosuppressed phase where the host is susceptible to secondary infections or is unable to clear existing infection. Specialized Pro-resolving Mediators (SPMs) are endogenously produced lipids which resolve infection by decreasing bacteria load and reducing systemic inflammatory response.

Resolvin T-series reduce neutrophil extracellular traps.

The newly identified 13-series (T-series) resolvins (RvTs) regulate phagocyte functions and accelerate resolution of infectious inflammation. Because severe acute respiratory syndrome coronavirus 2 elicits uncontrolled inflammation involving neutrophil extracellular traps (NETs), we tested whether stereochemically defined RvTs regulate NET formation. Using microfluidic devices capturing NETs in phorbol 12-myristate 13-acetate-stimulated human whole blood, the RvTs (RvT1-RvT4; 2.

Lipoxin A4 promotes reduction and antibiotic efficacy against Pseudomonas aeruginosa biofilm.

Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic bacterium commonly found in wound infections and airways of cystic fibrosis patients. P.

First total synthesis of the pro-resolving lipid mediator 7(),12(),13()-Resolvin T2 and its 13()-epimer.

The first total synthesis of the pro-resolving lipid mediator 7(),12(),13()-Resolvin T2 [7(), 12(), 13()-RvT2] and its 13()-epimer, derived from n-3 docosapentaenoic acid (n-3 DPA), are described. 7(), 12(), 13()-RvT2 and its 13()-epimer were obtained by total synthesis using a chiral pool strategy to introduce the chiral centers. C7 was generated from -(-)-1,2,4-butanetriol in both molecules and the C12 and C13 centers were generated from L-(+)-ribose and D-(-)-arabinose respectively.

First total syntheses of the pro-resolving lipid mediators 7(),13(),20()-Resolvin T1 and 7(),13()-Resolvin T4.

The first total syntheses of the pro-resolving lipid mediators 7(),13(),20()-Resolvin T1 [7(),13(),20()-RvT1] and 7(),13()-Resolvin T4 [7(),13()-RvT4], derived from n-3 docosapentaenoic acid (n-3 DPA), are described. 7(),13(),20()-RvT1 was prepared from 7(),13()-RvT4 via an enzymatic lipoxidase reaction. 7(),13()-RvT4 was obtained by total synthesis where the chiral centers at C7 and C13 where introduced by a Noyori transfer hydrogenation and a chiral pool strategy respectively.

Identification and Complete Stereochemical Assignments of the New Resolvin Conjugates in Tissue Regeneration in Human Tissues that Stimulate Proresolving Phagocyte Functions and Tissue Regeneration.

Resolvin conjugates in tissue regeneration (RCTRs) are new chemical signals that accelerate resolution of inflammation, infection, and tissue regeneration. Herein, using liquid chromatography-tandem mass spectrometry-based metabololipidomics, we identified RCTRs in human spleen, lymph node, bone marrow, and brain. In human spleen incubated with Staphylococcus aureus, endogenous RCTRs were increased along with conversion of deuterium-labeled docosahexaenoic acid, conferring pathway activation.

New maresin conjugates in tissue regeneration pathway counters leukotriene D-stimulated vascular responses.

Resolution of acute inflammation is governed, in part, by lipid mediator class switching from proinflammatory eicosanoids to specialized proresolving mediators, including a recently identified new pathway of mediators, termed maresin conjugates in tissue regeneration (MCTR), which includes MCTR1, MCTR2, and MCTR3. Here, we addressed whether each MCTR can impact the known vascular actions of cysteinyl leukotrienes. Leukotriene D (LTD; 1.

Maresin conjugates in tissue regeneration biosynthesis enzymes in human macrophages.

Macrophages are central in coordinating immune responses, tissue repair, and regeneration, with different subtypes being associated with inflammation-initiating and proresolving actions. We recently identified a family of macrophage-derived proresolving and tissue regenerative molecules coined maresin conjugates in tissue regeneration (MCTR). Herein, using lipid mediator profiling we identified MCTR in human serum, lymph nodes, and plasma and investigated MCTR biosynthetic pathways in human macrophages.

An Acute Retinal Model for Evaluating Blood Retinal Barrier Breach and Potential Drugs for Treatment.

A low-cost, easy-to-use and powerful model system is established to evaluate potential treatments that could ameliorate blood retinal barrier breach. An inflammatory factor, histamine, is demonstrated to compromise vessel integrity in the cultured retina through positive staining of IgG outside of the blood vessels. The effects of histamine itself and those of candidate drugs for potential treatments, such as lipoxin A4, are assessed using three parameters: blood vessel leakage via IgG immunostaining, activation of Müller cells via GFAP staining and change in neuronal dendrites through staining for MAP2.

Lipoxin A4 augments host defense in sepsis and reduces Pseudomonas aeruginosa virulence through quorum sensing inhibition.

Bacterial infections can quickly turn into sepsis, with its attendant clinical sequelae of inflammation, tissue injury, and organ failure. Paradoxically, sustained inflammation in sepsis may lead to immune suppression, because of which the host is unable to clear the existing infection. Use of agents that suppress the inflammatory response may accelerate host immune suppression, whereas use of traditional antibiotics does not significantly affect inflammation.

Identification and Actions of a Novel Third Maresin Conjugate in Tissue Regeneration: MCTR3.

Maresin conjugates in tissue regeneration (MCTR) are a new family of evolutionarily conserved chemical signals that orchestrate host responses to promote tissue regeneration and resolution of infections. Herein, we identified the novel MCTR3 and established rank order potencies and matched the stereochemistries of MCTR1, MCTR2 and MCTR3 using material prepared by total organic synthesis and mediators isolated from both mouse and human systems. MCTR3 was produced from endogenous substrate by E.

Effects of Lipoxin A4 on antimicrobial actions of neutrophils in sepsis.

In sepsis, hyperactivation of neutrophils can lead to tissue injury. Later, neutrophil dysregulation with reduced levels of migration, decreased apoptosis and inadequate phagocytosis may impair the host׳s ability to clear infection. Lipoxin A4 (LXA4) is a pro-resolution lipid mediator which reduces neutrophil migration and inflammatory mediator expression.

Lipoxin A(4) promotes more complete inflammation resolution in sepsis compared to stable lipoxin A(4) analog.

In sepsis, excessive inflammation may lead to organ injury or a paradoxical immunosuppressed state where the host is unable to clear preexisting infection. Resolution of inflammation is the process which restores tissue homeostasis and ensures that a chronic cycle of infection/inflammation does not occur. Lipoxin A4 (LXA4) is one of a family of lipid mediators with novel inflammation resolution activity.

Lipoxin a4 increases survival by decreasing systemic inflammation and bacterial load in sepsis.

Sepsis is characterized by systemic inflammation with release of a large amount of inflammatory mediators. If sustained, this inflammatory response can lead to multiple organ failure and/or immunoparalysis. In the latter condition, the host may be susceptible to opportunistic infections or be unable to clear existing infections.

Oxidative stress early in pregnancy and pregnancy outcome.

The objectives of this study were to determine whether oxidative stress early in pregnancy influenced pregnancy outcome. A combination of assays were used for exogenous and endogenous anti-oxidants together with two well accepted biomarkers for oxidative stress, the urinary excretion of 8-iso-PGF(2alpha) (a biomarker marker for lipid oxidation, n=508) and 8-oxo-7,8 dihydro-2 deoxyguanosine (8-OHdG, a biomarker for DNA oxidation, n=487). The two biomarkers tracked different pregnancy outcomes.

Release of the lipid peroxidation marker 8-epi-prostaglandin F2 alpha from isolated gill pavement cells.

The aim of the present study was to evaluate oxidative injury in gill pavement cells (GPCs) from fathead minnow (Pimephales promelas) using F2-isoprostane (F2-iP) release as an index of lipid peroxidation. Cells were isolated from pooled gill tissue by collagenase treatment, mechanical sieving, and Percoll density gradient centrifugation. Baseline levels of 8-epi-prostaglandin F2 alpha (8-epi-PGF2 alpha) were measured by incubating GPCs in physiological buffer (10(6) cells/ml) and enzyme immunoassay.

Tissue lead concentration during chronic exposure of Pimephales promelas (fathead minnow) to lead nitrate in aquarium water.

The fathead minnow is a useful species for evaluating the toxicity of wastewater effluents. While this fish is widely used for "survival" studies of metal toxicity, little or no work has been done on the tissue distribution of metals in fathead minnows. To determine the distribution of tissue lead, aquarium studies were conducted for several weeks with fish maintained in soft synthetic freshwater.